Balance between survivin, a key member of the apoptosis inhibitor family, and its specific antibodies determines erosivity in rheumatoid arthritis

• Rheumatoid arthritis (RA) is a highly heterogeneous disease with respect to its joint destructivity. The reasons underlying this heterogeneity are unknown. Deficient apoptosis in rheumatoid synovial tissue has been recently demonstrated. We have therefore decided to study the synovial expression of survivin, a key member of the apoptosis inhibitor family. The levels of survivin and antibodies against survivin were assessed by an ELISA in matched blood and synovial fluid samples collected from 131 RA patients. Results were related to joint erosivity at the time of sampling. Monocytes were transfected with survivin anti-sense oligonucleotides and were assessed for their ability to produce inflammatory cytokines. Survivin levels were significantly higher in patients with destructive disease as compared with in RA patients displaying a non-erosive disease. High survivin levels were an independent prognostic parameter for erosive RA. In contrast, high levels of antibodies against survivin were found in patients with non-erosive RA, and were negatively related to erosivity. Survivin levels in RA patients were influenced by treatment, being significantly lower among patients treated with disease-modifying anti-rheumatic drugs. Specific suppression of survivin mRNA resulted in downregulation of IL-6 production. We conclude that survivin determines the erosive course of RA, whereas survivin antibodies lead to a less aggressive course of the disease. These findings together with decreased survivin levels upon disease-modifying anti-rheumatic drug treatment, and the downregulation of inflammatory response using survivin anti-sense oligonucleotides, suggest that extracellular survivin expression mediates the erosive course of joint disease whereas autoimmune responses to the same molecule, manifested as survivin targeting antibodies, mediate protection.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Adolescent

Adult

Aged

Aged

80 and over

Antirheumatic Agents/therapeutic use

Apoptosis

Arthritis

Rheumatoid/blood/drug therapy/*immunology/pathology

Autoantibodies/biosynthesis/*immunology

Autoantigens/genetics/*immunology/metabolism

Autoimmune Diseases/blood/drug therapy/*immunology/pathology

Cells

Cultured/metabolism

Cytokines/biosynthesis

Disease Progression

Extracellular Fluid/metabolism

Female

Humans

Immunoglobulin G/biosynthesis/immunology

Immunoglobulin M/biosynthesis/immunology

Interleukin-6/secretion

Joints/*pathology

Male

Microtubule-Associated Proteins/genetics/*immunology/metabolism

Middle Aged

Monocytes/metabolism/secretion

Neoplasm Proteins/genetics/*immunology/metabolism

Oligodeoxyribonucleotides

Antisense/genetics

Predictive Value of Tests

Prognosis

Synovial Fluid/*metabolism

Thionucleotides/genetics

Transcription

Genetic

Transfection

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)